Persistent infections of human gamma-herpesviruses, Epstein-Barr virus (EBV or HHV-4) and Kaposi's sarcoma-associated herpesvirus (KSHV or HHV-8), are associated with several malignancies, which frequently develop in immunodeficiency virus (HIV)-infected AIDS patients and often found in their oral cavities. Through co-evolution with hosts, herpesviruses have acquired many strategies to counteract various aspects of the type interferon (IFN) responses, strongly indicating a powerful selective pressure from type I IFNs on the virus to antagonize it for successful infection. Type I IFNs are not only the major anti-viral effector of innate immunity but also important for the development of long-term memory adaptive responses. The overall hypothesis is that the ability to evade the type I IFN response is critical for effective viral growth in a host and that removal f the anti-IFN ability from the virus leads to a highly attenuated but immunogenic virus suitable for vaccination. To test the hypothesis, the following specific aims will be pursued: 1) to elucidate the mechanisms by which the viral genes inhibit type I IFN signaling, 2) to determine the biological significance of anti-IFN genes in vitro and in vivo, and 3) to test a rational therapeutc vaccine strategy by selective inactivation of viral immune evasion genes. The long-term goal is to develop strategies for preventing and treating cancers associated with persistent infections of KSHV and EBV. Accomplishment of the above aims, which is an important step towards achievement of the long-term goal, will demonstrate the feasibility of the therapeutic vaccine approach and establish a foundation for future pre-clinical studies in the KSHV primate model. Moreover, elucidating the anti-IFN function of a group of conserved viral proteins may reveal potential targets for therapeutic measures.